A failure of neuroprotective redox signalling from skeletal muscle to motor neurons leads to loss of motor units with ageing

从骨骼肌到运动神经元的神经保护性氧化还原信号传导失败，导致运动单位随着衰老而丧失

• 批准号: BB/I004076/1
• 负责人: Malcolm Jackson
• 金额: $ 46.08万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004076%2F1
• 关键词: failure; neuroprotective; redox; signalling; skeletal

The loss of skeletal muscle mass that occurs as we age leads to a significant decline in muscle strength and this is a major factor leading to the physical frailty seen in the elderly. Frailty is a major contributor to many health care problems and poor quality of life and results in increased risk of falls, hypothermia, incontinence and lack of independence. The bulk of our muscle declines by ~40% between the ages of 50 and 70 years regardless of the amount of exercise that is undertaken. Most current approaches to preserve muscle function during ageing try to improve the function of the muscle that remains in the elderly and are based on exercise training regimens, but the loss of muscle cells is associated with a loss of the motor nerves that stimulate the muscle to contract and there is no evidence that these can be replaced by exercise training. Thus exercise-based approaches can optimise the remaining muscle in the elderly, but cannot replace the motor nerves that are already lost. It is currently unknown whether the loss of the motor nerves precedes and leads to loss of the muscle or whether the reverse occurs. It appears that damage to tissues by highly reactive substances called free radicals or reactive oxygen species (ROS) may play an important role in the processes of ageing. Skeletal muscle cells have sophisticated systems that allow them to increase their protection against ROS during exercise, but this process appears to fail during ageing and contributes to the age-related loss of muscle cells. It is not known whether similar protective systems exist in the motor nerves, but some data indicate that muscle cells release substances that stimulate an increased protection against ROS in the motor nerves and hence helps to maintain their vaibility. Interventions to support these system might therefore help maintain the function of motor nerves during ageing. This possibility will be tested in a project that will use a combination of cell culture and mouse models. Muscle cells and motor nerve cells will be co-cultured to determine whether contracting muscle cells release substances that act on motor neurons to upregulate their defences against ROS and then the effect of ageing on this process will be examined in young and old mice. Our group has previously shown that aged mice with a genetic modification to improve their muscle defences against ROS show an improvement in muscle function. This project will determine whether this same genetic modification also improves the function of motor nerves. Finally the project will identify the substances that mediate these protective effects since they may be potential targets for future intervention studies to maintain motor nerve and muscle function in ageing.

随着年龄的增长，骨骼肌质量下降，导致肌肉力量显着下降，这是导致老年人身体虚弱的一个主要因素。虚弱是造成许多医疗保健问题和生活质量差的主要原因，并导致跌倒、体温过低、失禁和缺乏独立性的风险增加。无论进行多少运动，我们的大部分肌肉在 50 岁至 70 岁之间都会下降约 40%。目前大多数在衰老过程中保持肌肉功能的方法都试图改善老年人保留的肌肉功能，并且基于运动训练方案，但肌肉细胞的损失与刺激肌肉收缩的运动神经的丧失有关，并且没有证据表明这些可以通过运动训练来替代。因此，基于运动的方法可以优化老年人剩余的肌肉，但无法替代已经丧失的运动神经。目前尚不清楚运动神经的丧失是否先于肌肉的丧失并导致肌肉的丧失，或者是否会发生相反的情况。自由基或活性氧 (ROS) 等高活性物质对组织的损害似乎在衰老过程中发挥着重要作用。骨骼肌细胞拥有复杂的系统，使它们能够在运动过程中增强对活性氧的保护，但这一过程似乎会在衰老过程中失败，并导致与年龄相关的肌肉细胞损失。目前尚不清楚运动神经中是否存在类似的保护系统，但一些数据表明，肌肉细胞释放的物质可以刺激运动神经增强对活性氧的保护，从而有助于维持其可用性。因此，支持这些系统的干预措施可能有助于在衰老过程中维持运动神经的功能。这种可能性将在一个结合使用细胞培养和小鼠模型的项目中进行测试。肌肉细胞和运动神经细胞将被共培养，以确定收缩的肌肉细胞是否释放作用于运动神经元的物质，从​​而上调其对ROS的防御，然后在年轻和年老的小鼠中检查衰老对此过程的影响。我们的研究小组之前已经证明，经过基因改造以提高肌肉对 ROS 的防御能力的老年小鼠的肌肉功能有所改善。该项目将确定同样的基因改造是否也能改善运动神经的功能。最后，该项目将确定介导这些保护作用的物质，因为它们可能是未来干预研究的潜在目标，以维持衰老过程中的运动神经和肌肉功能。

项目成果

The effect of lengthening contractions on neuromuscular junction structure in adult and old mice.

• DOI: 10.1007/s11357-016-9937-7
• 发表时间: 2016-08
• 期刊: AGE
• 作者: Vasilaki, Aphrodite;Pollock, Natalie;Giakoumaki, Ifigeneia;Goljanek-Whysall, Katarzyna;Sakellariou, Giorgos K.;Pearson, Timothy;Kayani, Anna;Jackson, Malcolm J.;McArdle, Anne
• 通讯作者: McArdle, Anne

The role of attenuated redox and heat shock protein responses in the age-related decline in skeletal muscle mass and function.

• DOI: 10.1042/ebc20160088
• 发表时间: 2017-07
• 期刊: Essays in biochemistry
• 影响因子: 6.4
• 作者: A. Mcardle;M. Jackson

Ageing-induced changes in the redox status of peripheral motor nerves imply an effect on redox signalling rather than oxidative damage.

• DOI: 10.1016/j.freeradbiomed.2016.02.008
• 发表时间: 2016-05
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: McDonagh B;Scullion SM;Vasilaki A;Pollock N;McArdle A;Jackson MJ
• 通讯作者: Jackson MJ